PAH Treatment (Group 1)
Definition
PAH treatment is the risk-adapted use of vasodilator, remodelling and advanced therapies in Group 1 pulmonary arterial hypertension. It is guided by serial risk assessment rather than haemodynamics alone, and it applies to Group 1 disease only — Group 2 PH has no approved pulmonary-vascular therapy, Group 3 has a single Class IIb option, and Group 4 follows the CTEPH algorithm. The strategy is treat-to-target: assess risk at diagnosis, choose initial therapy matched to that risk, reassess at 3–6 months, and escalate or refer for transplantation when low-risk status is not achieved. (sources/PHT-ESC-2022, rating: very high)
Key Concepts
Assessment Before Treatment
- Right heart catheterisation is mandatory before starting PAH therapy; it confirms pre-capillary physiology (mPAP >20 mmHg, PAWP ≤15 mmHg, PVR >2 WU) and separates post-capillary PH. (sources/PHT-ESC-2022, rating: very high)
- Acute vasoreactivity testing is indicated in idiopathic, heritable and drug-induced PAH (Class I) and determines eligibility for calcium channel blockers; it is not indicated in other PH forms. See concepts/Right-Heart-Catheterization. (sources/PHT-ESC-2022; sources/hemodynamic-hf-pht-aha-2026, rating: very high)
- Risk stratum at diagnosis sets the initial regimen. The 2022 ESC/ERS model uses 3 strata at diagnosis and 4 at follow-up. See concepts/PAH-Risk-Stratification. (sources/PHT-ESC-2022)
- Low-risk treatment target: WHO-FC I/II, 6MWD >440 m, normal NT-proBNP, RAP <8 mmHg, cardiac index ≥2.5 L/min/m², stroke volume index ≥38 mL/m² and mixed venous oxygen saturation >65%. (sources/PHT-ESC-2022)
- Severe haemodynamic impairment at intermediate risk — RAP ≥20 mmHg, cardiac index <2.0 L/min/m², stroke volume index <31 mL/m² and/or PVR ≥12 WU — may justify initial triple therapy rather than dual combination. (sources/PHT-ESC-2022)
- Reassess every 3–6 months with WHO-FC, 6MWD, NT-proBNP and echocardiography, with RHC as clinically indicated. (sources/PHT-ESC-2022)
General Measures
- Supervised exercise training: Class I/A (upgraded from IIa) — a multicentre RCT in 116 PAH/CTEPH patients showed a +34.1 m improvement in 6MWD. (sources/PHT-ESC-2022, rating: very high)
- Diuretics: Class I/C for signs of RV failure and fluid retention. (sources/PHT-ESC-2022)
- Long-term oxygen: Class I/C when PaO₂ <8 kPa (60 mmHg). (sources/PHT-ESC-2022)
- Iron deficiency: Class I/C — intravenous iron for anaemia; repletion without anaemia is Class IIb. (sources/PHT-ESC-2022)
- Anticoagulation: Class IIb, individualised only — not generally recommended, potentially harmful in SSc-PAH and with conflicting evidence in IPAH. (sources/PHT-ESC-2022)
- ACE inhibitors, ARBs, ARNIs, SGLT2 inhibitors, beta-blockers and ivabradine: Class III unless required by a comorbidity such as hypertension, CAD, left heart failure or arrhythmia. (sources/PHT-ESC-2022)
- Pregnancy is strongly discouraged — maternal mortality 11–25% even with modern therapy. ERAs and riociguat are contraindicated (Class III/B); calcium channel blockers, PDE5 inhibitors and prostacyclin analogues are considered safe. See concepts/mWHO-Classification. (sources/PHT-ESC-2022)
- Never stop PAH therapy perioperatively — abrupt withdrawal of an ERA, PDE5 inhibitor or prostacyclin causes acute decompensation and death. See concepts/Perioperative-Cardiovascular-Assessment. (sources/periop-aha-2024, rating: very high)
Vasoreactive Disease — the Calcium Channel Blocker Pathway
- Positive acute vasoreactivity test: a fall in mPAP ≥10 mmHg to an absolute value ≤40 mmHg with maintained or increased cardiac output. (sources/hemodynamic-hf-pht-aha-2026, rating: very high)
- Only ~10% of IPAH/HPAH/DPAH patients are vasoreactive, and the response is predictive only in those three subtypes. (sources/PHT-ESC-2022, rating: very high)
- Vasoreactivity agents: inhaled nitric oxide, inhaled iloprost and intravenous epoprostenol are Class I; adenosine is no longer recommended because of AV block, bronchospasm and hypotension. (sources/hemodynamic-hf-pht-aha-2026)
- Calcium channel blockers: Class I/C — high-dose nifedipine, diltiazem, amlodipine or felodipine, with full reassessment including RHC at 3–6 months. (sources/PHT-ESC-2022)
- Adequate CCB response is WHO-FC I/II with mPAP <30 mmHg and PVR <4 WU at reassessment; CCBs are Class III in non-responders because of hypotension, syncope and RV failure. (sources/PHT-ESC-2022)
Non-Vasoreactive Disease — Initial Combination Therapy
| Risk at diagnosis |
Initial therapy |
Class |
| Low or intermediate |
ERA + PDE5 inhibitor |
I/B |
| Low or intermediate — specific pair |
Ambrisentan + tadalafil (AMBITION) |
I |
| Low or intermediate — specific pair |
Macitentan + tadalafil |
I (new in 2022) |
| Low or intermediate — other pairs |
Other ERA + PDE5 inhibitor combinations |
IIa |
| Intermediate with severe haemodynamic impairment |
Triple therapy including IV/SC prostacyclin may be considered |
— |
| High |
Triple therapy including parenteral prostacyclin plus early transplant evaluation |
— |
- The initial-combination recommendation is Class I/B for low-to-intermediate-risk IPAH, HPAH and DPAH; the evidence base for this table is those three subtypes. (sources/PHT-ESC-2022, rating: very high)
- Bosentan + sildenafil is Class III (downgraded from IIb) — not recommended, despite the class-level recommendation for ERA + PDE5i combination. (sources/PHT-ESC-2022)
- Selexipag, an oral prostacyclin receptor agonist, is approved for PAH combination therapy. (sources/PHT-ESC-2022)
Drug Classes and Agents
| Class |
Agents |
Route |
Place in therapy |
| Endothelin receptor antagonists (ERA) |
Ambrisentan, bosentan, macitentan |
Oral |
Backbone of initial combination |
| PDE5 inhibitors |
Sildenafil, tadalafil |
Oral |
Backbone of initial combination |
| Prostacyclin analogues |
Epoprostenol, treprostinil, iloprost |
IV, subcutaneous or inhaled |
High-risk initial triple therapy or escalation |
| IP receptor agonist |
Selexipag |
Oral |
Combination therapy |
| Activin signalling inhibitor |
Sotatercept |
Subcutaneous every 21 days |
Add-on for residual risk |
- ERA and PDE5 inhibitor use is supported at class level; bosentan + sildenafil is the exception at Class III. (sources/PHT-ESC-2022, rating: very high)
- Prostacyclin analogues are available by intravenous, subcutaneous and inhaled routes; parenteral prostacyclin is the recommended component of high-risk initial triple therapy and of escalation. (sources/PHT-ESC-2022; sources/PHT-RVsupport-WSPH-2019, rating: high)
Escalation, Sotatercept and Advanced Therapy
- Escalation trigger: intermediate-high or high risk at the 3–6-month reassessment → add parenteral prostacyclin or evaluate for lung transplantation. (sources/PHT-ESC-2022, rating: very high)
- Sotatercept is an ACTRIIA-Fc fusion protein that sequesters activins, GDF8 and GDF11, correcting the activin/GDF versus BMP imbalance that drives vascular remodelling; it is complementary to vasodilators because it targets structure rather than tone. It is given subcutaneously every 21 days, starting at 0.3 mg/kg and escalating to 0.7 mg/kg. See entities/Sotatercept. (sources/sotatercept-zenith-nejm-2025, rating: very high)
- STELLAR (WHO-FC II/III, n=323, stable background therapy): +34.4 m 6MWD, improved PVR, PA compliance, NT-proBNP and RV function, with an 84% reduction in clinical worsening events. (sources/rv-failure-aha-2026, rating: very high)
- ZENITH (WHO-FC III/IV, REVEAL Lite 2 ≥9, n=172, maximum tolerated double/triple therapy): stopped early; primary composite HR 0.24 (17.4% vs 54.7%), PAH hospitalisation 9.3% vs 50.0%, all-cause death 8.1% vs 15.1% (HR 0.42, not significant after early-stopping alpha adjustment). (sources/sotatercept-zenith-nejm-2025)
- HYPERION (WHO-FC II/III, diagnosed <1 year, REVEAL Lite 2 ≥6 or COMPERA 2.0 ≥2, n=320): clinical worsening HR 0.24 (10.6% vs 36.9%), NNT 5 at 12 months; deaths were balanced (4.4% vs 3.8%), so the benefit is functional rather than a mortality effect. (sources/sotatercept-hyperion-nejm-2025, rating: very high)
- Sotatercept safety: epistaxis (44% in ZENITH), telangiectasia (26%), increased haemoglobin (13%) and thrombocytopenia (14%); no excess serious AEs in ZENITH. (sources/sotatercept-zenith-nejm-2025)
- Transplant referral and listing: refer at intermediate/high risk or REVEAL >7 on therapy, progressive disease, need for parenteral prostacyclin, high-risk variants or secondary organ dysfunction; list at high risk or REVEAL ≥10 when expected 1-year medical mortality exceeds post-transplant mortality. See concepts/Lung-Transplantation-PAH. (sources/PHT-RVsupport-WSPH-2019, rating: high)
- ECMO as a bridge: VA-ECMO or PA–LA support for refractory RV failure, with awake ECMO preferred where feasible. See concepts/ECLS-in-PH. (sources/PHT-RVsupport-WSPH-2019)
- Acute RV failure in ICU: avoid intubation and fluid loading, use IV prostacyclin for afterload reduction, consider dobutamine or milrinone, and use vasopressin or norepinephrine for vasopressor support. See concepts/Right-Ventricular-Failure. (sources/PHT-RVsupport-WSPH-2019)
Special Populations and Contexts
Contradictions / Open Questions
- The initial-combination evidence base is narrower than its use: the Class I/B recommendation comes from IPAH, HPAH and DPAH, yet the same regimen is widely applied to SSc-PAH, CHD-PAH and other Group 1 subtypes without trial evidence in those groups. (sources/PHT-ESC-2022, rating: very high)
- Class-level endorsement conflicts with a specific Class III pair: ERA + PDE5i combination is Class I/B, but bosentan + sildenafil is Class III, so the recommendation cannot be applied by class alone. (sources/PHT-ESC-2022)
- Sotatercept first-line use is unresolved: STELLAR, ZENITH and HYPERION all required stable background therapy, so its role before ERA/PDE5i combination is unknown. (sources/sotatercept-hyperion-nejm-2025, rating: very high)
- Sotatercept's benefit differs by disease stage and survival remains unproven: ZENITH's mortality HR 0.42 did not reach the prespecified alpha after early stopping, whereas HYPERION's early-disease benefit was functional with balanced deaths. (sources/sotatercept-zenith-nejm-2025; sources/sotatercept-hyperion-nejm-2025)
- ESC risk strata and REVEAL Lite 2 thresholds are not mapped: parenteral prostacyclin escalation is triggered by ESC intermediate-high/high risk, while sotatercept trials used REVEAL Lite 2 ≥9 (ZENITH) and ≥6 or COMPERA 2.0 ≥2 (HYPERION). No prospective mapping exists. (sources/sotatercept-zenith-nejm-2025; sources/sotatercept-hyperion-nejm-2025)
- The 4-strata follow-up model has not been prospectively validated: the intermediate-low/intermediate-high split is expert consensus, not outcome-validated. (sources/PHT-ESC-2022)
- Anticoagulation in IPAH remains unresolved: downgraded to Class IIb despite meta-analyses suggesting survival benefit, with no RCT data and possible harm in SSc-PAH. (sources/PHT-ESC-2022)
- The lower diagnostic threshold has no treatment evidence: patients with mPAP 21–24 mmHg and PVR 2–3 WU now meet the PH definition but were excluded from every PAH drug trial. (sources/PHT-ESC-2022)
Connections
Sources